Related Experiment Videos
Neuroprotection of the developing brain by systemic administration of vasoactive intestinal peptide derivatives
P Gressens1, L Besse, P Robberecht
1Service de Neuropédiatrie and Institut National de la Santé et de la Recherche Médicale CRI 97-01, Hôpital Robert-Debré, Paris, France. pierre.gressens@rdb.ap-hop-paris.fr
Insights
Vasoactive intestinal peptide (VIP) analogs show promise in preventing white matter damage in newborn mice, a model for periventricular leukomalacia (PVL). These VIP analogs offer neuroprotection against excitotoxic brain injury, suggesting potential therapeutic applications for premature infants.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Periventricular leukomalacia (PVL) is a major cause of cerebral palsy in premature infants.
- Excitotoxicity, driven by increased glutamate release, is implicated in PVL pathogenesis.
- Vasoactive intestinal peptide (VIP) demonstrates protective effects against excitotoxic brain injury.
Purpose of the Study:
- To evaluate the neuroprotective efficacy of systemically administered VIP analogs against ibotenate-induced excitotoxic white matter lesions in newborn mice.
- To assess the therapeutic window for VIP analog administration in a preclinical model of PVL.
Main Methods:
- Newborn mice were subjected to intracerebral ibotenate injection to induce white matter lesions.
- Systemic administration of VIP analogs (RO-25-1553, stearyl-norleucine-VIP) or VIP was performed immediately, 8, or 12 hours post-ibotenate.
- Histological analysis was used to quantify the reduction in white matter cyst formation.
Main Results:
- VIP analogs RO-25-1553 and stearyl-norleucine-VIP significantly reduced ibotenate-induced white matter cysts by up to 87% and 84%, respectively.
- Systemic VIP administration was not protective, unlike the analogs.
- Neuroprotection was observed even when VIP analogs were administered 8 and 12 hours after the excitotoxic insult.
Conclusions:
- Systemically administered VIP analogs, particularly RO-25-1553 and stearyl-norleucine-VIP, effectively protect developing white matter from excitotoxic injury in a murine model.
- These VIP analogs demonstrate a prolonged therapeutic window, suggesting their potential as novel therapeutic agents for PVL in high-risk premature infants.
Abstract:
Periventricular leukomalacia (PVL), a necrotic and often cystic lesion of the cerebral white matter occurring in very premature babies, is the leading cause of cerebral palsy in this population. Increased glutamate release and the excitotoxic cascade thus triggered may be critical factors in the development of PVL. The glutamatergic analog ibotenate injected intracerebrally into newborn mice produces white matter cysts that mimic human PVL. Concomitant injection of vasoactive intestinal peptide (VIP), a trophic factor, protects the white matter against excitotoxic lesions. The goal of the present study was to assess the protective properties of systemically injected VIP analogs against ibotenate-induced excitotoxic white matter lesions in newborn mice. VIP analogs were selected on the basis of their low susceptibility to endopeptidases and their potential ability to cross biological membranes. RO-25-1553, a long-lasting cyclic VIP analog, and stearyl-norleucine-VIP, a fatty derivative of VIP, reduced ibotenate-induced white matter cysts by up to 87% and 84%, respectively, when injected i.p. immediately after ibotenate. By comparison, i.p. coadministration of VIP and ibotenate was not protective against the excitotoxic insult. Furthermore, RO-25-1553 and stearyl-norleucine-VIP still induced significant neuroprotection of the developing white matter when injected systemically 8 and 12 h, respectively, after ibotenate, establishing these peptides as therapeutic agents in this murine model. VIP analogs may have therapeutic potential in human premature babies at high risk for PVL.